Immediate Release Compositions and Methods For Delivering Drug Formulations Using Weak Acid Ion Exchange Resins In Abnormally High pH Environments

ABSTRACT

Multi-layer solid oral dosage immediate release and extended release compositions and methods for delivering drugs in abnormally high pH environments wherein the extended release layer is formed from a drug resinate of a strong acid ion-exchange resin and a release rate retarding polymer compressed together.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.13/506,512 filed Apr. 23, 2012 which originated from parent applicationSer. No. 12/807,434 filed Sep. 3, 2010 and since issued as U.S. Pat. No.8,187,617 B2. The disclosures of patent application Ser. No. 12/807,434and U.S. Pat. No. 8,187,617 B2 are herein incorporated by reference tothe extent not incompatible herewith.

BACKGROUND OF THE INVENTION

The present invention relates to novel pharmaceutical compositions thatprovide both immediate drug release (IR) and extended drug release evenat higher than normal stomach pH levels. The formulations are based ondrug resinates of weak acid ion exchange resins.

Formulations containing weak acid ion exchange resins are frequentlyused for immediate release of pharmaceutical agents in a patient'sstomach. However, release from weak acid resins is slowed and/or reducedat higher than normal stomach pH levels. High pH levels could occur ifthe patient is taking medications such as proton pump inhibitors (PPIs)or has a disease state that induces hypochlorhydria or achlorhydria. Ineither case, a weak acid formulation may not release the medicament at arate or to an extent adequate to achieve the desired therapeutic effect.

Approximately 60 million prescriptions were written for PPIs in 2006.Additionally, in the U.S., another 10 million people were reported tohave self medicated with PPIs in 2008. Furthermore, about one in threeadults used antacids on a regular basis. Collectively, these statisticssuggest that close to 100 million people in the U.S. could be taking adrug that could significantly interfere with the release profile of aweak acid ion exchange resinate formulation. The history of prior artdosage forms indicates that a serious need has existed for novel anduseful solid oral dosage forms that provide the immediate releaseproperties of weak acid IER formulations when administered to a patientwith stomach pH environments at about 1.5 to 2.0 and above. This needwas met in part by commonly owned U.S. Pat. No. 8,187,617. It was shownthat weak acid resinates can be formulated to have immediate releasecharacteristics at pH levels above about 1.5 to 2.0 by adding a releaseenhancing agent to the formulation to increase the rate and extent ofdrug release from the formulation.

It is also desirable in many instances that a drug be released in asustained manner over a period of about 8 hours. Both immediate release(IR) and extended release (ER) of one or more drugs may be needed.

An extended release preparation is usually achieved using a release rateretarding coating over the drug-resin complex using polymers like,hydroxypropyl methylcellulose (hypromellose), ethyl cellulose (EC)Eudragit™ polymers (manufactured by Degussa Rohm Pharma Polymers ofGermany), polyvinyl alcohol either alone or in combination over thedrug-resin particles/beads.

However, achieving extended release by coating drug-resinparticles/beads is beset with multiple issues like, (i) non-uniformcoating over individual particles/beads, (ii) agglomeration of theparticles/beads during coating and rupturing of the coat duringsubsequent sieving/sifting operation, (iii) issues in reproducibility ofin vitro drug release kinetics due to (i) & (ii) above, and (iv)cracking of the coating during a tablet compression process. For thereasons mentioned above extended release polymer coated particles/beadscan cause dose dumping on oral administration. For reason (iv) extendedrelease beads are usually filled into capsules rather than beingtableted.

Surprisingly and unexpectedly, an extended release profile can becreated without the use of coated particles.

SUMMARY OF THE INVENTION

As described in commonly owned U.S. Pat. No. 8,187,617 B2, it has beenfound that by adding a release enhancing agent with a strong affinityfor the ionic resin to a weak acid resin drug formulation, much morerapid and complete release of a resinated drug can be attained inabnormal gastric fluid than otherwise would occur without the presenceof the release enhancing agent, in abnormal human gastric fluid whereinthe pH is much higher than normal due to the use of drugs such as PPI orthe presence of disease states such as H. pylori or atrophic gastritisthat can lead to hypochlorhydria and achlorhydria.

Thus, one can attain the rapid release properties of weak acid resinateswhile retaining the low sensitivity to pH change associated strong acidresins by adding a release enhancing agent to the weak acid drugformulation.

It is also desirable in many instances that a drug be released in asustained manner over a period of about 8 hours. Both immediate release(IR) and extended release (ER) of one or more drugs may be needed.

Immediate release is defined as at least 80% release of apharmaceutically active agent within 45 minutes in a standarddissolution apparatus according to the USP 34 NF 26 section 711.

An extended release drug preparation is usually achieved using a releaserate retarding coating over the drug-resin complex. However, as notedabove, achieving extended release by coating drug-resin particles/beadsis beset with multiple issues.

Surprisingly and unexpectedly, an extended release profile can becreated without the use of coated particles. Instead of coating theparticles, the present invention uses wet and dry granulation techniquesto generate a dry blend of granules of particles/beads of a drugresinate mixed with a release rate retarding polymer. By compressingthis blend of particles/beads of drug resinate with these release rateretarding polymers, an extended release profile is obtained whilesignificant reduction in processing complexity is realized. Morespecifically the need for spray coating of the ionic exchange resinateis avoided while at the same time extended release behavior is assuredby having the ion exchange resinate enveloped in the blend of polymericmaterial. It is well known to those versed in the technology thatparticle coating is a time intensive as well as a problematic process.This is avoided by using the polymeric material and ion exchangeresinate blend during compression of the desired dosage form.

In a first embodiment, the invention is a multi-layer solid oralpharmaceutical composition comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and        -   (b) a release-enhancing agent consisting of FeCl₃;    -   (ii) at least a second distinct layer comprising:        -   (a) a drug selected from the group consisting of said first            pharmaceutically active agent and a second pharmaceutically            active agent, said drug being bound to a strong acid ion            exchange resin to form a strong acid ion-exchange resinate;            and        -   (b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and, wherein        said release of the drug from said strong acid resinate        continues over a period of at least 8 hours after ingestion.

In a second embodiment, the invention is method of treating a patientwith a stomach pH of at least about 1.5 comprising administration of amultilayer solid oral dosage form, said dosage form comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii) at least a second distinct layer comprising:        -   (a) a drug selected from the group consisting of said first            pharmaceutically active agent and a second pharmaceutically            active agent, said drug being bound to a strong acid ion            exchange resin to form a strong acid ion-exchange resinate;            and,        -   b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and,        wherein release of the drug from said strong acid resinate        continues over a period of at least 8 hours after ingestion.

In a third embodiment, the invention is a method of treating a patienthaving a first condition and a second condition with a pharmaceuticallyactive agent effective for treating said second condition, said methodcomprising the step of administering a solid oral dosage pharmaceuticalcomposition, said solid oral dosage pharmaceutical compositioncomprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and,        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii.) at least a second distinct layer comprising:        -   (a) pharmaceutically active agent selected from the group            consisting of said first pharmaceutically active agent and a            second pharmaceutically active agent, said pharmaceutically            active agent bound to a strong acid ion exchange resin to            form a strong acid ion-exchange resinate; and,        -   b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; wherein release        of the drug from said strong acid resinate continues over a        period of at least 8 hours after ingestion; and        wherein said first condition is selected from the group        consisting of Helicobacter pylori infection, atrophic gastritis,        hypochlorhydria and achlorhydria in the stomach; and wherein        said second condition is a condition other than said first        condition.

In a fourth embodiment, the invention is a method of treating a patientwherein the patient has within the past 24 hours been administered acompound selected from the group consisting of a proton pump inhibitor,an H2 receptor antagonist, and an antacid, said method comprising thestep of administering a solid oral dosage pharmaceutical composition,said solid oral dosage pharmaceutical composition comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and,        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii.) at least a second distinct layer comprising:        -   (a) pharmaceutically active agent selected from the group            consisting of said first pharmaceutically active agent and a            second pharmaceutically active agent, said pharmaceutically            active agent bound to a strong acid ion exchange resin to            form a strong acid ion-exchange resinate, and        -   (b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and,        wherein release of the drug from said strong acid resinate        continues over a period of at least 8 hours after ingestion.

In a fifth embodiment, the invention is method of delivering apharmaceutically active agent to a patient, said method comprisingorally administering a solid oral dosage composition comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii) at least a second distinct layer comprising:        -   (a) pharmaceutically active agent selected from the group            consisting of said first pharmaceutically active agent and a            second pharmaceutically active agent, said pharmaceutically            active agent bound to a strong acid ion exchange resin to            form a strong acid ion-exchange resinate; and,        -   b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and, wherein        release of the drug from said strong acid resinate continues        over a period of at least 8 hours after ingestion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of one embodiment of a tablet of theinvention, consisting of IR and ER layers and a unbound drug layer.

FIG. 2 shows the release profile of hydrocodone from a three layertablet of the invention in simulated gastrointestinal dissolution.

FIG. 3 shows release profile of pseudoephedrine from the same threelayer tablet as in FIG. 2 in simulated gastrointestinal dissolution.

FIG. 4 shows the release profile in simulated gastrointestinaldissolution of hydrocodone from a gelatin capsule containing only a neatresinate formed from hydrocodone bitartrate and the strong acidion-exchange resin Amberlite™ IRP69.

FIG. 5 shows the release profiles of codeine and pseudoephedrine from athree layer tablet of the invention in simulated gastrointestinaldissolution.

FIG. 6 shows the release profile in simulated gastrointestinaldissolution of codeine from a gelatin capsule containing only a neatresinate formed from codeine and the strong acid ion-exchange resinAmberlite™ IRP69.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the invention is a multi-layer solid oralpharmaceutical composition comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and        -   (b) a release-enhancing agent consisting of FeCl₃:    -   (ii) at least a second distinct layer comprising:        -   (a) a drug selected from the group consisting of said first            pharmaceutically active agent and a second pharmaceutically            active agent, said drug being bound to a strong acid ion            exchange resin to form a strong acid ion-exchange resinate;            and        -   (b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and, wherein        said release of the drug from said strong acid resinate        continues over a period of at least 8 hours after ingestion.

In a second embodiment, the invention is method of treating a patientwith a stomach pH of at least about 1.5 comprising administration of amultilayer solid oral dosage form, said dosage form comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii.) at least a second distinct layer comprising:        -   (a) a drug selected from the group consisting of said first            pharmaceutically active agent and a second pharmaceutically            active agent, said drug being bound to a strong acid ion            exchange resin to form a strong acid ion-exchange resinate;            and,        -   b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and, wherein        release of the drug from said strong acid resinate continues        over a period of at least 8 hours after ingestion.

The pharmaceutical compositions of the invention are characterized byfaster, and/or more complete, drug release compared to a weak acid resinformulation without the release enhancing agent in pH environments at orabove about 1.5 to 2.0. When administered to a patient, therelease-enhancing agent results in immediate release of thepharmaceutically active agent(s) from the weak acid ion exchange resinin pH environments at or above about 1.5 to 2.0.

The multilayer pharmaceutical compositions of the invention are formedas compressed tablets. However, the tablets of the invention can be ofminiature dimension such that many miniature tablets can be insertedinto a capsule of a size suitable for oral ingestion. The inventionincludes such capsules.

The drug release kinetics of weak acid resins can be affected by higherpH levels in the gastric fluid such that the rate and/or extent of drugrelease can be greatly reduced. Adding a release enhancing agent to aweak acid formulation is useful for assuring that the resinated drug isreleased from an IER formulation when stomach acid is reduced oreliminated (hypochlorhydria and achlorhydria) by disease states such asHelicobacter (H.) pylori Infection or atrophic gastritis.

By adding a release enhancing agent with a strong affinity for the ionicresin to the weak acid resin drug formulation can facilitate release ofthe resinated drug in abnormal human gastric fluid where the pH is muchhigher than normal due to the use of drugs such as proton pumpinhibitors or the presence of disease states such as H. pylori infectionor atrophic gastritis. The immediate release component comprises a firstdistinct layer of a tablet of the Invention.

Weak acid ion exchange resins useful in the invention include, forexample, the potassium salt of carboxylated polymethacrylic resins suchas Amberlite™ IRP88 (CAS Registry Number 39394-76-5) manufactured by DowChemical, and DOWEX MAC-3, manufactured by Dow Chemical but other weakacid ion exchange resins may be used.

The release-enhancing agent can be, for example, a highly solubleinorganic salt (e.g., FeCl₃, FeCl2, Fe₂(SO₄)₃, CaCl₂, NaCl, MgCl₂) or anorganic base (e.g., thymine, guanine, or cytosine).

The pharmaceutical composition includes at least a second distinctlayer. This second layer comprises: (a) a pharmaceutical active agentbound to strong acid ion exchange resin forming a resinate; and, (b) arelease rate retarding polymer susceptible to gastrointestinaldissolution to slow and extend release of the drug contained in said atleast second layer; wherein said strong acid ion-exchange resinate andsaid polymer are compressed together.

The strong acid ion exchange resin in the second layer can be bound tothe same or different pharmaceutically active agent as the weak acid ionexchange resin.

Strong acid ion exchange agents useful in the invention includesulfonated polystyrenic resins such as Amberlite IRP69, and Dowex 88,but other strong acid ion exchange resins may be used.

The release rate retarding polymer can be any of a number of non-toxicmaterials susceptible to gastrointestinal dissolution. It may be apolymer conventionally used in coatings for extending drug release suchas, but not limited to, hydroxypropyl methylcellulose (hypromellose),ethyl cellulose (EC), polyethylene oxide, Eudragit™ polymers(manufactured by Degussa Rohm Pharma Polymers of Germany), the Carbopol™polymers (manufactured by Lubrizol Corp), polyvinyl alcohol,hydrogenated vegetable oil, methacrylate copolymers, polyacrylic acid,and their combinations with one another or with other suitable polymers.

The tablets of the invention may comprise three or more layers. Apharmaceutical active agent in the third, or yet additional layers, maybe bound to ion-exchange resin, or it may be unbound, i.e., not bound toan ion-exchange resin.

The weight ratio of drug to ion-exchange resin in either a weak acid orstrong acid resinate can be varied to adjust a release profile.Preferably, the drug to resin weight ratio in a resinate is from about1:0.5 to about 1:10. More preferably, the drug to resin weight ratio ina resinate is from about 1:0.75 to about 1:5. Most preferably, the drugto resin weight ratio in a resinate is from about 1:1 to about 1:3.

The drug/ion-exchange resinates employed in the inventive compositionsand methods are produced by known methods, as for example as describedin Example 1 of U.S. Pat. No. 8,187,617 B2. After formation of aresinate, the resinate is preferably granulated and sieved intoparticles that pass a screen size of about 1000 microns (#18 screen).Preferably, resinate particles pass a 841 micron (#20 screen), and mostpreferably pass a screen size of about 420 microns (#40 screen).

The weight ratio of release enhancing agent to drug resinate in the IRlayer is preferably from about 1:50 to about 1:1. More preferably, therelease enhancing agent to drug resinate weight ratio is from about 1:20to about 1:2.

The weight ratio of drug in first distinct layer (IR layer) to the drugin the second distinct layer (ER layer) can also be varied to adjust arelease profile. The weight ratio of IR drug to ER drug is preferablyfrom about 10:90 to about 90:10. More preferably, the weight ratio of IRdrug to ER drug is from about 20:80 to about 80:20; yet more preferablyfrom about 30:70 to about 70:30; and most preferably from about 40:60 toabout 60:40.

The weight of release rate retarding polymer in an ER layer ispreferably from about 5 to about 90 percent by weight of the layer, andmore preferably from about 10 to about 80 percent by weight of thelayer.

Compression of an ER layer preferably occurs during the tablettingoperation. Tabletting is at a compression force of from about 100Newtons to about 300 Newtons. The person of ordinary skill in the artwill adjust the tabletting pressure to obtain the desired tabletthickness and strength.

By “release-enhancing agent” is meant an agent that, when added to adrug resin formulation, increases the rate and/or the extent of drugrelease than would otherwise occur without the release-enhancing agentin the same formulation.

By “pharmaceutically active agent” is meant agents other than foodarticles that are intended to diagnose, cure, mitigate, treat or preventdisease in man or other animals or that are intended to affect thestructure or any function of the body of man or other animals that arephysiologically acceptable. The agent could be a combination of drugtherapies as well as a single agent.

By “physiologically acceptable” is meant those substances that areadequately tolerated without causing unacceptable negative side effects.

By “ion exchange resin” is meant an insoluble solid matrix that carriesexchangeable ions with either a positive or negative charge. Thetrapping of ions takes place only with simultaneous releasing of otherions. Ions are exchanged in stoichiometrically equivalent amounts ofother ions with the same electrical charge when the ion exchangematerial is in contact with an electrolyte solution.

By “resinate” is meant the complex formed when a drug exchanges an ionwith a resin particle in the stoichiometric process described above anda drug/resin compound is formed.

By “weak acid ion exchange resin” is meant in a weak acid resin theionizable group introduced to the polymer is a carboxylic acid (COOH) asopposed to the sulfonic acid group (SO₃H) used in strong acid resins.These resins behave similarly to weak organic acids so are weaklydissociated i.e. have fewer ions available for exchange.

By “immediate release” (IR) is meant that the pharmacologically activeagent is released from the IR portion of the formulation such that 80%,85%, 90%, or even 95% of the pharmaceutically active agent in the IRportion is released within 45 minutes when dissolution is measuredaccording to the USP 34 NF 26 section 711.

By “extended release” is meant that the pharmaceutically active agent isreleased from the formulation at a controlled rate such that theformulation allows for a reduction in dosing frequency as compared tothat presented by a conventional dosage form, e.g. an immediate releasedosage form.

By “strong acid ion exchange resin” is meant a cation exchange resin inwhich the ion exchange groups are completely dissociated at all pHs. Asan example, in a strong acid resin the ionizable group introduced to thepolymer is a sulfonic acid group (SO₃H) as opposed to the carboxylicacid (COOH) used in weak acid resins.

Release-Enhancing Agents

The drug-containing weak acid ion exchange resins of the invention areformulated with release-enhancing agents. These release-enhancing agentsresult in immediate release of the drug from the weak acid ion exchangeresins in pH environments at or above 2.0. Examples of suitablerelease-enhancing agents are:

Inorganic Agents:

FeCl₃, Fe₂(SO₄)₃

CaCl₂

MgCl₂

FeCl₂

Organic Agents:

Thymine

Guanine

Cytosine

The release rate retarding polymer can be any of a number of non-toxicmaterials susceptible to gastrointestinal dissolution. It may be apolymer conventionally used in coatings for extending drug release suchas, but not limited to, hydroxypropyl methylcellulose (hypromellose),ethyl cellulose (EC), polyethylene oxide, Eudragit™, polymers(manufactured by Degussa Rohm Pharma Polymers of Germany), the Carbopol™polymers (manufactured by Lubrizol Corp), polyvinyl alcohol,hydrogenated vegetable oil, and their combinations with one another orwith other suitable polymers.

Pharmaceutically Active Agents

The invention features methods and compositions for immediate release ofpharmaceutically active agents using a weak acid ion exchange resin.

Examples of such pharmaceutically active agents suitable for thecompounds and methods of the inventions are:

A: Anti-tussives, e.g., benzonatate, caramiphen edisylate,chlophedianol, codeine, dextromethorphan hydrobromide, hydrocodone,levopropoxyphene, morphine codeine, ethylmorphine, dihydrocodeine,benzylmorphine, laudanum, dihydroisocodeine, nicocodeine, nicodicodeine,hydrocodone, hydromorphone, acetyldihydrocodeine, thebacon, diamorphine(heroin), acetylmorphone, noscapine, and pholcodine.

B: Narcotic analgesics, e.g., codeine, oxycodone, hydrocodone,diamorphine, pethidine, morphine, oxymorphone, nalorphine, naloxone,naltrexone, opium, hydromorphone, nicomorphine, dihydrocodeine, andpapaveretum.

C: Decongestants, e.g., pseudoephedrine hydrochloride, phenylephrinebitartrate, phenylephrine hydrochloride and pseudoephedrine sulfate.

D: Non-steroidal anti-inflammatory drugs, e.g., aspirin, magnesiumsalicylate, diclofenac, etodolac, indometacin, nabumetone, sulindac,tolmetin, ibuprofen, ketoprofen, mefenamic acid, meclofenamic acid,phenylbutazone, piroxicam, meloxicam, celecoxib, parecoxib, rofecoxib,valdecoxib, and naproxen sodium.

E: Anti-emetic drugs, e.g., dolasetron, granisetron, ondansetron,tropisetron, palonosetron, mirtazapine, metoclopramide, cyclizine,diphenhydramine, dimenhydrinate, meclizine, promethazine, andhydroxyzine.

F: Anti-histamines, e.g., diphenhydramine, loratadine, desloratadine,meclizine, fexofenadine, pheniramine, cetirizine, promethazine,brompheniramine, clemastine fumarate and chlorpheniramine.

G: Proton pump inhibitors (PPI), e.g., omeprazole, esomeprazole,pantoprazole, lansoprazole, and rabeprazole.

H: H2 Antagonists, e.g., cimetidine, ranitidine, and famotidine.

I: Anti-depressants, e.g., citalopram, escitalopram, fluoxetine,fluvoxamine, paroxetine, sertraline, desvenlafaxine, duloxetine,milnacipran, venlafaxine, atomoxetine, mazindol, reboxetine, viloxazine,amitriptyline, clomipramine, doxepin, imipramine, trimipramine,desipramine, nortriptyline, protriptyline, moclobemide, pheneizine, andselegiline.

J: Tranquilizers, e.g., amobarbital, pentobarbital, secobarbital,phenobarbital, clonazepam, diazepam, estazolam, flunitrazepam,lorazepam, midazolam, nitrazepam, oxazepam, triazolam, temazepam,chlordiazepoxide, and alprazolam.

K: Anti-convulsants, e.g., felbamate, carbamazepine, oxcarbazepine,vigabatrin, progabide, tiagabine, topiramate, gabapentin, pregabalin,ethotoin, and phenytoin.

L: Hypnotics, e.g., zolpidem, zaleplon, zopiclone, and eszopiclone.

M: Muscle relaxants, e.g., methocarbamol, carisoprodol, chlorzoxazone,cyclobenzaprine, gabapentin, metaxalone, and orphenadrine.

N: Anti-psychotics, e.g., haloperidol, droperidol, chlorpromazine,fluphenazine, perphenazine, prochlorperazine, thioridazine,trifluoperazine, mesoridazine, promazine, triflupromazine,levomepromazine, methotrimeprazine, pimozide, chlorprothixene,flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine,risperidone, quetiapine, ziprasidone, amisulpride, asenapine, andpaliperidone.

O: Anti-microblals, e.g., EDTA, zinc compounds, triclosan, domiphen,cetyl pyridium chloride, domiphen bromide, fluorides, alexidine, andoctenidine.

P: Anti-diarrheals, e.g., bismuth subsalicylate and loperamide.

R: CNS stimulants, e.g., caffeine, cocaine, and amphetamines.

S: Attention Deficit and Hyperactivity Disorder drugs, e.g.,methylphenidate, dextroamphetamine sulfate, amphetamine, and atomoxetinehydrochloride.

The invention also includes methods and compositions for deliveringcombinations of pharmaceutically active compounds. Examples of suchcombinations are:

A: an anti-tussive and an antihistamine

B: an anti-tussive and a decongestant

C: an anti-tussive and an analgesic

D: an anti-tussive and an NSAID

E: an anti-tussive and an antihistamine and a decongestant

F: an anti-tussive and an antihistamine and an analgesic

G: an anti-tussive and an antihistamine and an NSAID

H: an anti-tussive and an antihistamine and a decongestant and ananalgesic

I: a muscle relaxant and an analgesic

J: a muscle relaxant and an NSAID

K: a muscle relaxant and an analgesic and an NSAID

L: a PPI and an NSAID

M: an H2 antagonist and an NSAID

N: a PPI and an analgesic

O: an H2 antagonist and an analgesic

Dosage Forms

Suitable dosage forms include a multiple layer compressed tablet and acapsule containing multiple miniature compressed tablets.

In a third embodiment, the invention is a method of treating a patienthaving a first condition and a second condition with a pharmaceuticallyactive agent effective for treating said second condition, said methodcomprising the step of administering a solid oral dosage pharmaceuticalcomposition, said solid oral dosage pharmaceutical compositioncomprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and,        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii) at least a second distinct layer comprising:        -   (a) pharmaceutically active agent selected from the group            consisting of said first pharmaceutically active agent and a            second pharmaceutically active agent, said pharmaceutically            active agent bound to a strong acid ion exchange resin to            form a strong acid ion-exchange resinate; and,        -   (b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; wherein release        of the drug from said strong acid resinate continues over a        period of at least 8 hours after ingestion; and        wherein said first condition is selected from the group        consisting of Helicobacter pylori infection, atrophic gastritis,        hypochlorhydria and achlorhydria in the stomach; and wherein        said second condition is a condition other than said first        condition.

In a fourth embodiment, the invention is a method of treating a patientwherein the patient has within the past 24 hours been administered acompound selected from the group consisting of a proton pump inhibitor,an H2 receptor antagonist, and an antacid, said method comprising thestep of administering a solid oral dosage pharmaceutical composition,said solid oral dosage pharmaceutical composition comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and,        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base:    -   (ii) at least a second distinct layer comprising:        -   (a) pharmaceutically active agent selected from the group            consisting of said first pharmaceutically active agent and a            second pharmaceutically active agent, said pharmaceutically            active agent bound to a strong acid ion exchange resin to            form a strong acid ion-exchange resinate, and        -   (b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer:    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711: and, wherein        release of the drug from said strong acid resinate continues        over a period of at least 8 hours after ingestion.

In a fifth embodiment, the invention is method of delivering apharmaceutically active agent to a patient, said method comprisingorally administering a solid oral dosage composition comprising:

-   -   (i) a first distinct layer comprising:        -   (a) a first pharmaceutically active agent bound to a weak            acid ion exchange resin to form a weak acid ion-exchange            resinate; and        -   (b) a release-enhancing agent selected from the group            consisting of an inorganic salt and an organic base;    -   (ii.) at least a second distinct layer comprising:        -   (a) pharmaceutically active agent selected from the group            consisting of said first pharmaceutically active agent and a            second pharmaceutically active agent, said pharmaceutically            active agent bound to a strong acid ion exchange resin to            form a strong acid ion-exchange resinate; and,        -   b) a release rate retarding polymer susceptible to            gastrointestinal dissolution to slow and extend release of            the drug contained in said at least second layer;    -   wherein said strong acid ion-exchange resinate and said polymer        have been compressed together; and        wherein said pharmaceutical composition is capable of immediate        release of said first pharmaceutically active agent from said        weak acid resinate at a pH of at least 1.5, immediate release        being defined as at least 80% release of said pharmaceutically        active agent within 45 minutes in a standard dissolution        apparatus according to USP 34 NF 26 section 711; and, wherein        release of the drug from said strong acid resinate continues        over a period of at least 8 hours after ingestion.

EXAMPLES

Each of the compositions of the examples below are useful for oraladministration for conditions such as normal stomach pH of about 1.5 to2.0 or higher, Helicobacter pylori infection, atrophic gastritis,hypochlorhydria and achlorhydria. The compositions of the examples arealso useful for patients who have been administered a proton pumpinhibitor, or a H2 receptor antagonist or an antacid within thepreceding 24 hours.

Example 1

The following example of the invention is a tablet consisting of threedistinct layers containing in total 10 mg equivalent of hydrocodonebitartrate and 120 mg of pseudoephedrine.

A resinate of hydrocodone bitartrate (HCBT) and the weak acidion-exchange resin AMBERUTE™ IRP88 was prepared as described in Example1 of U.S. Pat. No. 8,187,617 B2. The drug loading in the resinate wastested and showed 33% drug load or approximately 33 mg of HCBT per 100mg of resinate. The resinate was granulated and sieved through a #40screen.

A second resinate of hydrocodone bitartrate was prepared, but this timewith the strong acid ion-exchange resin AMBERLITE™ IRP69. The procedurefor preparing the resinate was substantially the same as in Example 1 ofU.S. Pat. No. 8,187,617 B2, but using the strong acid resin in place ofthe weak acid resin. The drug loading in the resinate was tested andshowed 33% drug load or approximately 33 mg of HCBT per 100 mg ofresinate.

The HCBT resinate was granulated and sieved through a #40 screen anddivided into two parts. The first part this HCBT/IR69 resinate was usedin forming a three layer tablet as described below. The second part ofthis HCBT/IR69 resinate was used in Comparative Example 1 as will bedescribed below.

Tablet Composition

A three layer tablet was formed having the composition shown in Table Iconsisting of a hydrocodone immediate release layer (identified as layer“A”), a hydrocodone extended release layer (layer “B”) and apseudoephedrine layer (layer “C”). The pseudoephedrine was unbound, i.e,not bound to an ion-exchange resin.

TABLE I Ingredients Qty (mg/tab) % (w/w) IR Layer (A HydrocodoneResinate (IRP-88) eq to 2 mg Hydrocodone Bitartrate) HydrocodoneResinate (Amberlite IRP-88) 6.00 0.7 eq to 2.0 mg Hydrocodone BitartrateFerric chloride 2.00 0.2 Microcrystalline Cellulose 119.00 13.2 LactoseMonohydrate 100.00 11.1 Stearic acid 3.00 0.4 Sodium Starch Glycolate15.00 1.7 Colloidal Silicon dioxide 2.50 0.3 Magnesium Stearate 2.50 0.3Total (A) 250.00 Hydrocodone Resinate (IRP-69) eq to 8 mg HydrocodoneBitartrate ER Layer (B) Hydrocodone Resinate (Amberlite IRP-69) 24.002.7 eq to 8.0 mg Hydrocodone Bitartrate Lactose Monohydrate 55.00 6.1Microcrystalline Cellulose 70.0 7.8 Hypromellose 120.00 13.3 PovidoneK30 10.00 1.1 Calcium Chloride 15.0 1.7 Colloidal Silicon dioxide 3.00.3 Magnesium Stearate 3.0 0.3 Total (B) 300.0 Pseudoephedrine HCl layerEq to 120 mg Layer (C) Pseudoephedrine HCl 120.00 13.3 HydrogenatedVegetable Oil 120.00 13.3 Mannitol 35.00 3.9 Lactose Monohydrate 67.007.4 Colloidal Silicon dioxide 5.00 0.6 Magnesium Stearate 3.00 0.3 Total(C) 350.00 Total (A) + (B) + (C) Tri-layer 900.00 100.0

Tablet Preparation

The tablet was prepared as follows below. It will be noted that thepreparation procedure did not involve coating of the drug resinate.

A. Hydrocodone Immediate Release (IR) Layer

-   1. The microcrystalline cellulose and lactose monohydrate were    sieved through a #40 (420 micron) screen and thoroughly mixed    together.-   2. The hydrocodone resinate of the weak acid ion-exchange resin,    ferric chloride, stearic acid, sodium starch glycolate and colloidal    silicon dioxide were thoroughly mixed together and sieved through a    #40 screen.-   3. The blend of step 2 was gradually added to the blend of step 1    with continued mixing.-   4. Magnesium stearate lubricant was sieved through a #40 screen and    thoroughly mixed into the blend of step 3.

B. Hydrocodone Extended Release (ER) Layer

-   5. The lactose monohydrate and about half of the hypromellose were    mixed together and granulated with purified water.-   6. The wet granules of step 5 were dried and sieved through a #20    screen.-   7. The first part of the HCBT/IRP69 resinate prepared above, the    microcrystalline cellulose, the remaining portion of the    hypromellose, the calcium chloride, the colloidal silicon dioxide    and the lactose monohydrate were individually sieved through a #40    screen, thoroughly mixed together and the mixture re-sieved through    a #40 screen.-   8. The granules of step 6 were thoroughly mixed with the dry mix of    step 7.-   9. Magnesium stearate lubricant was sieved through a #40 screen and    thoroughly mixed into the blend of step 8.

C. Pseudoephedrine HCL Layer

-   10. The pseudoephedrine HCl and mannitol were thoroughly mixed    together and sieved through a #80 (177 micron) screen.-   11. The hydrogenated vegetable oil was melted at 70-80° C.-   12. The pseudoephedrine HCl and mannitol were slowly added to the    melted hydrogenated vegetable oil with continuous stirring and mixed    thoroughly. The mixture was then cooled to room temperature under    stirring.-   13. The cooled mixture of step 12 was milled through a co-mill    fitted with a #40 screen.-   14. The lactose monohydrate and colloidal silicon dioxide were    individually sieved through a #40 screen and thoroughly mixed    together.-   15. The mixture of step 14 was added to the granules of step 13 and    thoroughly mixed together.-   16. Magnesium stearate lubricant was sieved through a #60 screen and    thoroughly mixed into the blend of step 15.

Tri-Layer Compression

The lubricated blends of steps 4, 9 and 16 were fed to a rotary tabletcompression machine and compressed into tri-layer tablets using 13.30 mmround shape punches. The tablets were of 6.50±0.30 mm thickness, were of900±5% mg weight, and had a tablet breaking force of 225 N (200-250 N).

Example 2

A tri-layer tablet prepared as described in Example 1 was subjected tosimulated gastrointestinal dissolution testing in a standard dissolutionapparatus according to USP 34 NF 26 section 711. The measureddissolution profiles of hydrocodone and pseudoephedrine are shown belowin Table II and are plotted in FIGS. 2 and 3 respectively.

It will be seen that 29% of the total hydrocodone content of thetri-layer tablet (2.9/10 mg) was released in 45 minutes. While therelease from the IR component alone cannot be determined from thesedata, it is clear that the immediate release exceeded the totalhydrocodone loading of the IR layer.

It will also be seen that extended release of the hydrocodone continuedfor at least 8 hours. It is to be noted that this extended release wasaccomplished without having coated the drug resinate.

TABLE II Dissolution of Hydrocodone Resinate and Pseudoephedrine HClTri-layer Tablets 10 mg/120 mg Method: Paddle 50 rpm 900 mL. in 0.1N HClPercent Dissolution Time (Hr) Hydrocodone Bitartrate Pseudoephedrine HCl0 0 0 0.25 22 15 0.5 26 22 0.75 29 27 1 32 31 2 45 43 4 62 64 6 80 86 890 98 10 94 100 12 95 104

Comparative Example 1

Tabletting of the second part of the HCBT/IRP69 resinate prepared inExample 1 was attempted. However, the maximum pressure exerted by atablet press was insufficient to form a stable tablet of this resinate.Consequently, 24 mg from the second part of the HCBT/IRP69 resinateprepared in Example 1 was loaded into a gelatin capsule. This capsulecontaining only the neat resinate was subjected to simulatedgastrointestinal dissolution testing in a standard dissolution apparatusaccording to USP 34 NF 26 section 711.

The measured dissolution profile of hydrocodone is plotted in FIG. 4. Itis seen that the cumulative HCBT release from the neat resinate at theend of 45 minutes was 70 percent of 24 mg or 16.8 mg. This may becompared with 29% release of 30 mg or only 8.7 mg from the tri-layertablet even including the immediate release component.

Moreover, the HCBT release from the neat resinate had essentially endedafter about 2 hours whereas the HCBT release from the tri-layer tabletcontinued for at least 8 hours.

Both of these comparisons show the effectiveness of compressing amixture of a release rate retarding polymer with a drug/ion-exchangeresinate to form an extended release tablet or tablet layer.

Example 3

The following example of the invention is a tablet consisting of threedistinct layers containing in total 45 mg equivalent of codeine and 120mg of pseudoephedrine.

A resinate of codeine and the weak acid ion-exchange resin AMBERLITE™IRP88 was prepared in the manner described in Example 1 of U.S. Pat. No.8,187,617 B2 except that codeine was used in place of hydrocodone. Thedrug loading in the resinate was tested and showed approximately 46.3% %drug load or approximately 46.3 mg of codeine per 100 mg of resinate.The resinate was granulated and sieved through a #40 screen.

A second resinate of codeine was prepared, but this time with the strongacid ion-exchange resin AMBERLITE™ IRP69. The method of preparing theresinate was substantially the same as in Example 1 of U.S. Pat. No.8,187,617 B2, but using codeine in place of hydrocodone and using thestrong acid resin in place of the weak acid resin. The drug loading inthe resinate was tested and showed 46.8% drug load or approximately 46.8mg of codeine per 100 mg of resinate.

The codeine resinate was granulated and sieved through a #40 screen anddivided into two parts. The first part this codeine/IR69 resinate wasused in forming a three layer tablet as described below. The second partof this codeine/IR69 resinate was used in Comparative Example 2 as willbe described below.

Tablet Composition

A three layer tablet was formed having the composition shown in TableIII below consisting of a codeine immediate release layer (identified aslayer “A”), a codeine extended release layer (layer “B”) and apseudoephedrine layer (layer “C”).

Tablet Preparation

The codeine tri-layer tablet was prepared using the same steps describedin detail for the hydrocodone tri-layer tablet in Example 1 above.

Tri-Layer Compression

The lubricated blends of steps 4, 9 and 16 described above were fed to arotary tablet compression machine and compressed into tri-layer tabletsusing 13.30 mm round shape punches. The tablets were of 6.50±0.30 mmthickness, were of 935±5% mg weight, and had a tablet breaking force of190 N (170-210 N).

It will be noted that the preparation procedure did not involve coatingof the drug resinate.

TABLE III Ingredients Qty (mg/tab) % (w/w) IR layer (A Codeine Resinate(IRP-88) eq to 9 mg Codeine) Codeine Resinate (Amberlite IRP-88) 19.442.1 eq. to 9.0 mg Codeine Ferric chloride 1.2 0.1 MicrocrystallineCellulose 114.96 12.3 Sodium Starch Glycolate 5.00 0.5 LactoseMonohydrate 100.00 10.7 Colloidal Silicon dioxide 5.00 0.5 Stearic acid1.8 0.2 Magnesium Stearate 2.60 0.3 Total (A) 250.00 26.7 ER Layer (B)Codeine Resinate (IRP-69) eq to 36 mg codeine Codeine Resinate(Amberlite IRP-69) 77.00 8.2 eq. to 36.0 mg Codeine Hypromellose(intragranular) 75.00 8.0 Lactose Monohydrate 80.00 8.6 Calcium Chloride33.75 3.6 Hypromellose (extragranular) 40.00 4.3 MicrocrystallineCellulose 23.25 2.5 Colloidal Silicon dioxide 3.00 0.3 MagnesiumStearate 3.00 0.3 Total (B) 335.00 35.8 Layer (C) Pseudoephedrine HClLayer Eq to 120 mg Pseudoephedrine HCl 120.00 13.3 HydrogenatedVegetable Oil 120.00 13.3 Mannitol 35.00 3.9 Lactose Monohydrate 67.007.4 Colloidal Silicon dioxide 5.00 0.6 Magnesium Stearate 3.00 0.3 Total(C) 350.00 37.4 Total (A) + (B) + (C) Tri-layer 935.00 100.0

Example 4

A tri-layer tablet prepared as described in Example 3 was subjected tosimulated gastrointestinal dissolution testing in a standard dissolutionapparatus according to USP 34 NF 26 section 711. The measureddissolution profiles of codeine and pseudoephedrine are shown below inTable IV and are plotted in FIG. 4.

TABLE IV Dissolution of Codeine Resinate and Pseudoephedrine HClTri-layer Tablets 45 mg/120 mg Method: Paddle 50 rpm 900 mL. in 0.1N HClTime Codeine Pseudoephedrine HCL (hr) Percent Dissolution 0 0 0 0.25 2315 0.5 28 21 0.75 32 26 1 36 30 2 46 42 4 62 62 6 78 82 8 88 93 10 94 9712 96 98

It is seen that 32% of the total codeine content of the tri-layer tablet(14.4/45 mg) was released in 45 minutes. While the release from the IRcomponent alone cannot be determined from these data, it is clear thatthe immediate release exceeded the total codeine loading of the IRlayer.

It will also be seen that extended release of the codeine continued forat least 8 hours. It is to be noted that this extended release wasaccomplished without having coated the drug resinate.

Comparative Example 2

Tabletting of the second part of the codeine/IRP69 resinate prepared inExample 3 was attempted. However, the maximum pressure exerted by atablet press was insufficient to form a stable tablet of this resinate.Consequently, 77 mg from the second part of the codeine/IRP69 resinateprepared in Example 3 was loaded into a gelatin capsule. This capsulecontaining only the neat resinate was subjected to simulatedgastrointestinal dissolution testing in a standard dissolution apparatusaccording to USP 34 NF 26 section 711.

The measured dissolution profile of codeine is plotted in FIG. 6. It isseen that the cumulative codeine release from the neat resinate at theend of 45 minutes was about 82 percent of 77 mg or about 63 mg. this maybe compared with 32% release of 96.44 mg or only 30.8 mg from thetri-layer tablet even including the immediate release component.

Moreover, the codeine release from the neat resinate had essentiallyended after about 45 minutes whereas the HCBT release from the tri-layertablet continued for at least 8 hours.

Both of these comparisons show the effectiveness of compressing amixture of a release rate retarding polymer with a drug/ion-exchangeresinate to form an extended release tablet or tablet layer.

OTHER EMBODIMENTS

All publications, patent applications, and patents mentioned in thisspecification are herein incorporated by reference to the extent notincompatible herewith.

Various modifications and variations of the described method and systemof the invention will be apparent to those skilled in the art withoutdeparting from the scope and spirit of the invention. Although theinvention has been described in connection with specific desiredembodiments, it should be understood that the invention as claimedshould not be unduly limited to such specific embodiments. Indeed,various modifications of the described modes for carrying out theinvention that are obvious to those skilled in the fields of medicine,immunology, pharmacology, endocrinology, or related fields are intendedto be within the scope of the invention.

What is claimed is:
 1. A multi-layer solid oral pharmaceuticalcomposition comprising: (i) a first distinct layer comprising: (a) afirst pharmaceutically active agent bound to a weak acid ion exchangeresin to form a weak acid ion-exchange resinate; and (b) arelease-enhancing agent consisting of FeCl₃; (ii) at least a seconddistinct layer comprising: (a) a drug selected from the group consistingof said first pharmaceutically active agent and a secondpharmaceutically active agent, said drug being bound to a strong acidion exchange resin to form a strong acid ion-exchange resinate; and (b)a release rate retarding polymer susceptible to gastrointestinaldissolution to slow and extend release of the drug contained in said atleast second layer; wherein said strong acid ion-exchange resinate andsaid polymer have been compressed together and wherein saidpharmaceutical composition is capable of immediate release of said firstpharmaceutically active agent from said weak acid resinate at a pH of atleast 1.5, immediate release being defined as at least 80% release ofsaid pharmaceutically active agent within 45 minutes in a standarddissolution apparatus according to USP 34 NF 26 section 711; and,wherein said release of the drug from said strong acid resinatecontinues over a period of at least 8 hours after ingestion.
 2. Themulti-layer solid oral pharmaceutical composition of claim 1 having atleast three distinct layers, each said layer comprising pharmaceuticallyactive agents in a form selected from the group consisting ofion-exchange resinates and unbound pharmaceutically active agents. 3.The multi-layer solid oral pharmaceutical composition of claim 1 wheresaid first layer comprises a member of the group consisting ofhydrocodone bitartrate polacrilex weak acid resinate, codeine polacrilexweak acid resinate and dextromethorphan polacrilex weak acid resinate;and said second layer comprises a member of the group consisting ofhydrocodone polistirex strong acid resinate, codeine polistirex strongacid resinate and dextromethorphan polistirex strong acid resinate. 4.The multi-layer solid oral pharmaceutical composition of claim 2,wherein, at least one of said layers comprises an unboundpharmaceutically active agent.
 5. The multi-layer solid oralpharmaceutical composition of claim 4 wherein said first layer comprisesa member of the group consisting of hydrocodone bitartrate polacrilexweak acid resinate, codeine polacrilex weak acid resinate anddextromethorphan polacrilex weak acid resinate; and said second layercomprises a member of the group consisting of hydrocodone polistirexstrong acid resinate, codeine polistirex strong acid resinate anddextromethorphan polistirex strong acid resinate; and wherein a thirdlayer consists of an unbound pharmaceutically active agent.
 6. A methodof treating a patient with a stomach pH of at least about 1.5 comprisingadministration of a multilayer solid oral dosage form, said dosage formcomprising: (i) a first distinct layer comprising: (a) a firstpharmaceutically active agent bound to a weak acid ion exchange resin toform a weak acid ion-exchange resinate; and (b) a release-enhancingagent selected from the group consisting of an inorganic salt and anorganic base; (ii) at least a second distinct layer comprising: (a) adrug selected from the group consisting of said first pharmaceuticallyactive agent and a second pharmaceutically active agent, said drug beingbound to a strong acid ion exchange resin to form a strong acidion-exchange resinate; and, b) a release rate retarding polymersusceptible to gastrointestinal dissolution to slow and extend releaseof the drug contained in said at least second layer; wherein said strongacid ion-exchange resinate and said polymer have been compressedtogether; and wherein said pharmaceutical composition is capable ofimmediate release of said first pharmaceutically active agent from saidweak acid resinate at a pH of at least 1.5, immediate release beingdefined as at least 80% release of said pharmaceutically active agentwithin 45 minutes in a standard dissolution apparatus according to USP34 NF 26 section 711; and, wherein release of the drug from said strongacid resinate continues over a period of at least 8 hours afteringestion.
 7. The method of treating a patient with a stomach pH of atleast about 1.5 as in claim 6, wherein said patient has a firstcondition and a second condition, said first condition being selectedfrom the group consisting of Helicobacter pylori infection, atrophicgastritis, hypochlorhydria and achlorhydria in the stomach; and whereinsaid second condition is a condition other than said first condition. 8.The method of treating a patient with a stomach pH of at least about 1.5as in claim 6, wherein the patient has within the past 24 hours beenadministered a compound selected from the group consisting of a protonpump inhibitor, an H2 receptor antagonist.
 9. A method of delivering apharmaceutically active agent to a patient, said method comprisingorally administering a solid oral dosage composition comprising: (i) afirst distinct layer comprising: (a) a first pharmaceutically activeagent bound to a weak acid ion exchange resin to form a weak acidion-exchange resinate; and (b) a release-enhancing agent selected fromthe group consisting of an inorganic salt and an organic base; (ii.) atleast a second distinct layer comprising: (a) pharmaceutically activeagent selected from the group consisting of said first pharmaceuticallyactive agent and a second pharmaceutically active agent, saidpharmaceutically active agent bound to a strong acid ion exchange resinto form a strong acid ion-exchange resinate; and, b) a release rateretarding polymer susceptible to gastrointestinal dissolution to slowand extend release of the drug contained in said at least second layer;wherein said strong acid ion-exchange resinate and said polymer havebeen compressed together; and wherein said pharmaceutical composition iscapable of immediate release of said first pharmaceutically active agentfrom said weak acid resinate at a pH of at least 1.5, immediate releasebeing defined as at least 80% release of said pharmaceutically activeagent within 45 minutes in a standard dissolution apparatus according toUSP 34 NF 26 section 711; and, wherein release of the drug from saidstrong acid resinate continues over a period of at least 8 hours afteringestion.
 10. The multi-layer solid oral pharmaceutical composition ofclaim 1, wherein the release rate retarding polymer is selected from thegroup consisting of hydroxypropyl methylcellulose, ethyl cellulose,polyethylene oxide, polyvinyl alcohol, hydrogenated vegetable oil,methacrylate copolymers, polyacrylic acid, and their combinations. 11.The method of delivering a pharmaceutically active agent to a patient ofclaim 9, wherein the release rate retarding polymer is selected from thegroup consisting of hydroxypropyl methylcellulose, ethyl cellulose,polyethylene oxide, polyvinyl alcohol, hydrogenated vegetable oil,methacrylate copolymers, polyacrylic acid, and their combinations. 12.The method of treating a patient with a stomach pH of at least about 1.5of claim 6, wherein the release rate retarding polymer is selected fromthe group consisting of hydroxypropyl methylcellulose, ethyl cellulose,polyethylene oxide, polyvinyl alcohol, hydrogenated vegetable oil,methacrylate copolymers, polyacrylic acid, and their combination.